Effects of Indatraline and Buprenorphine on Self-Administration of Speedball Combinations of Cocaine and Heroin by Rhesus Monkeys Nancy K

Home , Indatraline, Quadazocine, Speedball (drug)

Effects of Indatraline and Buprenorphine on Self-Administration of Speedball Combinations of Cocaine and Heroin by Rhesus Monkeys Nancy K. Mello, Ph.D., and S. Stevens Negus, Ph.D.

The simultaneous intravenous (i.v.) administration of buprenorphine (0.10 and 0.18 mg/kg/day) significantly heroin and cocaine, called a “speedball,” is often reported reduced speedball self-administration in comparison to the clinically, and identification of effective pharmacotherapies saline treatment baseline (p Ͻ .01– .001), whereas the is a continuing challenge. We hypothesized that treatment same doses of each compound alone had no significant effect with combinations of a dopamine reuptake inhibitor, on speedball-maintained responding. Daily treatment with indatraline, and a mu partial agonist, buprenorphine, 0.56 mg/kg/day indatraline ϩ 0.18 mg/kg/day might reduce speedball self-administration by rhesus buprenorphine produced a significant downward shift in monkeys more effectively than either drug alone. Speedballs the speedball dose-effect curve (p Ͻ .01) and transient (0.01 mg/kg/inj cocaine ϩ 0.0032 mg/kg/inj heroin) and changes in food-maintained responding. These findings food (1 g banana pellets) were available in four daily suggest that medication mixtures designed to target both sessions on a second-order schedule of reinforcement [fixed the stimulant and opioid component of the speedball ratio (FR)4; variable ratio (VR)16:S]. Monkeys were combination may be an effective approach to polydrug treated for 10 days with saline or ascending dose abuse treatment. combinations of indatraline (0.001-0.032 mg/kg/day) and [Neuropsychopharmacology 25:104–117, 2001] buprenorphine (0.00032–0.01 mg/kg/day). Two © 2001 American College of Neuropsychopharmacology. combinations of indatraline (0.32 and 0.56 mg/kg/day) ϩ Published by Elsevier Science Inc.

KEY WORDS: Speedball, Cocaine, Heroin, Indatraline, secondary drug of abuse (NIDA 1999). The simulta- Buprenorphine, Drug self-administration, Dopamine neous intravenous administration of cocaine and her- reuptake inhibitor, Opioid partial agonist oin, often called a “speedball,” is one common form of Cocaine and heroin abuse continue to be major drug polydrug abuse (NIDA 1999; Schütz et al. 1994). Crack abuse problems in the United States (NIDA 1999). cocaine is sometimes dissolved with vinegar or lemon Treatment admission reports, emergency ward men- juice to permit intravenous injection alone, or in combi- tions, and mortality data indicate that among primary nation with heroin (NIDA 1999). It is obvious that mul- heroin abusers, cocaine is usually the most common tiple drug use presents a formidable challenge for medication-based treatment approaches. The currently approved pharmacotherapies for opioid abuse have been only moderately effective in reducing polydrug From the Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, MA abuse, and continued opioid and cocaine abuse by Address correspondence to: Nancy K. Mello, Ph.D., Alcohol and methadone-maintained patients is often reported (Con- Drug Abuse Research Center, Harvard Medical School-McLean delli et al. 1991; Kosten et al. 1989b; Schottenfeld et al. Hospital, 115 Mill Street, Belmont, MA 02478. Received 18 April 2000; revised 10 November 2000; accepted 30 1993, 1997). Treatment of concurrent cocaine and heroin November 2000. abuse is further complicated by the fact that there is no

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NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Speedball and Indatralime/Burprenorphine 105

effective pharmacotherapy for cocaine abuse alone alone and speedball self-administration, and therefore (Mendelson and Mello 1996). could not account for the increases in dopamine release The ways in which cocaine and heroin interact to during speedball self-administration (Hemby et al. 1999). maintain speedball abuse are poorly understood, but Treatment with opioid antagonists or dopamine an- most clinical studies suggest that opioids enhance the tagonists alone has not been effective in reducing subjective effects of cocaine. For example, methadone- speedball self-administration in preclinical studies. The maintained subjects (50 mg/day, p.o.) had greater posi- long-acting opioid antagonist naltrexone (3.2–1600 ␮g/ tive subjective responses (liking, good effect, rush) and kg, i.m.) dose-dependently decreased self-administra- cardiovascular responses to acute i.v. doses of cocaine tion of heroin alone (6.4 or 13 ␮g/kg/inj) and some (12.5–50 mg, i.v.) than opioid abusers who were not speedball combinations, but these effects were sur- maintained on methadone (Preston et al. 1996). Simi- mounted by increasing the dose of heroin (Rowlett et al. larly, subjects maintained on high methadone doses 1998). Acute treatment with naltrexone had no effect on (70–80 and 90–100 mg/day, p.o.) reported significantly cocaine (100 ␮g/kg/inj) self-administration (Rowlett et greater subjective responses (stimulated, liking, quality, al. 1998), and this finding was consistent with earlier good drug) to acute doses of i.v. cocaine (8 or 16 mg/70 studies of the effects of naltrexone on cocaine self- kg) than subjects maintained on lower methadone administration in rhesus monkeys (Mello et al. 1990, doses (20–60 mg/day, p.o.) (Foltin et al. 1995). 1993b) and in rats (Corrigall and Coen 1991). The effects

In clinical studies of speedballs, the subjective effects of naltrexone alone, and the dopamine D2 antagonist et- of cocaine and opioid (morphine or hydromorphone) iclopride alone, on speedball self-administration were combinations were usually greater than the subjective compared in rats (Hemby et al. 1996). Naltrexone (3.0– effects of either drug alone (Foltin and Fischman 1992; 30 mg/kg) antagonized the rate-suppressant effects of Walsh et al. 1996). The maximum response for subjec- the speedball combination, but the resulting speedball tive effect measures was similar after cocaine alone and dose-effect curve was not significantly different from cocaine and opioid combinations, and occurred within that for cocaine alone (Hemby et al. 1996). Acute ad- 1 to 2 min (Walsh et al. 1996). Although positive mood ministration of eticlopride (0.03–0.3 mg/kg) produced a scores were higher after speedball administration than downward shift in the speedball dose-effect curve that after either component drug alone, these effects were was more pronounced at high (18 ␮g) than low (5.4 ␮g) less than additive (Foltin and Fischman 1992; Walsh et doses of heroin in combination with cocaine (Hemby et al. 1996). In human polydrug abusers, speedball combi- al. 1996). The authors concluded that antagonism of nations usually produced a compound stimulus that in- both dopamine and opioid receptors may be necessary cluded aspects of both component drugs (Foltin and to significantly reduce speedball self-administration Fischman 1992). (Hemby et al. 1996). Preclinical studies also suggest that opioids may in- A combination of the dopamine antagonist flu- crease the abuse-related effects of cocaine. For example, penthixol and the opioid antagonist quadazocine was opioids usually increase the discriminative stimulus ef- more effective in reducing the discriminative stimulus fects of cocaine in squirrel monkeys (Rowlett and Speal- effects of speedballs by rhesus monkeys than either an- man 1998; Spealman and Bergman 1992, 1994) and in tagonist alone (Negus et al. 1998a). These findings led rhesus monkeys (Mello et al. 1995; Negus et al. 1998a). us to examine the effects of the same flupenthixol and Cocaine and heroin combinations produce robust rein- quadazocine combination on speedball self-administra- forcing and discriminative stimulus effects in rats and tion by rhesus monkeys (Mello and Negus 1999). We rhesus monkeys (Hemby et al. 1996, 1999; Mello and found that 10 days of treatment with a combination of Negus 1998; Mello et al. 1995; Negus et al. 1998a; flupenthixol and quadazocine reduced speedball self- Rowlett et al. 1998; Rowlett and Woolverton 1997). administration significantly in comparison to saline Moreover, cocaine and heroin may enhance each treatment, whereas the same doses of each antagonist other’s reinforcing and discriminative stimulus effects alone had no significant effect on speedball-maintained when administered in a speedball (Negus et al. 1998a; responding. These findings are consistent with the no- Rowlett and Woolverton 1997). Neurochemical find- tion that medication combinations may be a useful ap- ings suggest that self-administration of cocaine and proach to polydrug abuse treatment. However, the ef- heroin in combination has synergistic effects on extra- fects of this dopamine antagonist ϩ opioid antagonist cellular dopamine release at the nucleus accumbens in combination on speedball self-administration were not rats (Hemby et al. 1999). Dopamine levels measured by sustained over 10 days of treatment (Mello and Negus microdialysis remained at baseline levels during heroin 1999). Dopamine antagonists usually have transient ef- self-administration, increased by 400% during cocaine fects on cocaine self-administration, and these effects self-administration and increased by 1000% during are not prolonged by increasing the antagonist dose speedball self-administration (Hemby et al. 1999). Co- (Kleven and Woolverton 1990; Negus et al. 1996; Rich- caine dialysate levels were equivalent during cocaine ardson et al. 1994). One important limitation of antago-

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nist medications for clinical treatment of drug abuse 1993; Kosten et al. 1989a,b; Schottenfeld et al. 1993). In has been problems with patient retention (Mendelson rhesus monkeys, chronic treatment with buprenor- and Mello 1996). Naltrexone has been relatively inef- phine selectively reduced self-administration of cocaine fective in outpatient treatment because it could be dis- alone (Mello et al. 1989, 1990, 1992, 1993a,b) and heroin continued without precipitating withdrawal signs or alone (Mello et al. 1983; Mello and Negus 1998). How- symptoms, and it had no positive mood modulating ef- ever, in monkeys trained to self-administer speedballs, fects (National Research Council Committee on Clinical the effectiveness of buprenorphine varied as a function Evaluation of Narcotic Antagonists 1978; Schecter 1980). of the unit dose of cocaine in the speedball (Mello and Agonist-substitution type pharmacotherapies such Negus 1998). Buprenorphine (0.237 mg/kg/day) was as methadone and buprenorphine have been more ef- most effective when heroin was combined with a low fective than naltrexone in maintaining opioid-depen- (0.001 mg/kg/inj) or a high (0.10 mg/kg/inj) unit dose dent patients in treatment (Mello and Mendelson 1995; of cocaine on the ascending or descending limb of the O’Brien 1996). Given the transient effects of the flu- cocaine dose-effect curve. These findings are consistent penthixol ϩ quadazocine combination described above with our earlier reports that buprenorphine (0.237–0.70 (Mello and Negus 1999), we postulated that the combi- mg/kg/day) reduced self-administration of relatively nation of a long-acting monoamine reuptake inhibitor high unit doses of cocaine (0.05 and 0.10 mg/kg/inj) by indatraline, and a mu opioid partial agonist buprenor- rhesus monkeys (Mello et al. 1989, 1990, 1992, 1993a,b). phine, might be more effective in producing sustained Buprenorphine was least effective when heroin was decreases in speedball self-administration. The poten- combined with an intermediate unit dose of cocaine tial ability of this drug combination to reduce speedball (0.01 mg/kg/inj) that was at the peak of the dose-effect self-administration was suggested by our recent studies curve for cocaine alone (Mello and Negus 1998). of the effects of indatraline on cocaine self-administra- We now report that chronic treatment with an indatra- tion and discrimination (Negus et al. 1999) and our pre- line and buprenorphine combination reduced self-admin- vious studies of the effects of buprenorphine on co- istration of a speedball combination of 0.01 mg/kg/inj cocaine, heroin and speedball self-administration (Mello caine ϩ 0.0032 mg/kg/inj heroin more effectively than the and Mendelson 1995; Mello and Negus 1998). same doses of either indatraline or buprenorphine alone. The purpose of the present study was to compare the Moreover, a combination of indatraline and buprenor- effects of chronic treatment with indatraline and bu- phine produced a significant downward shift in the prenorphine alone, and in combination, on speedball speedball self-administration dose-effect curve. These self-administration by rhesus monkeys. Indatraline was findings extend our previous study of speedball treatment selected because it directly competes with cocaine for with a dopamine and opioid antagonist combination and binding sites on the dopamine, norepinephrine and se- further suggest that medication combinations may be a rotonin transporters and because it has a long duration useful approach to the treatment of speedball abuse. of action (Rothman and Glowa 1995; Negus et al. 1999). Moreover, some monoamine reuptake inhibitors produce some cocaine-like behavioral effects and alter co- METHODS caine self-administration in a manner consistent with Subjects the conclusion that they may substitute for cocaine’s reinforcing effects (Glowa et al. 1995a,b; Kleven and Koek Five rhesus monkeys (Macaca mulatta), one male (12241) 1998; Negus et al. 1999; see Rothman and Glowa 1995 and four females (075F, 89B211, 89B157, Ch701) were for review). Indatraline (0.1–0.56 mg/kg/day) pro- studied. Monkeys weighed between 6 and 12 kg and all duced dose-dependent and sustained decreases in co- had self-administered cocaine for at least one year before caine (0.0032–0.1 mg/kg/inj) self-administration by cocaine ϩ heroin speedball combinations were made rhesus monkeys (Negus et al. 1999). Indatraline (0.1–1.0 available. Speedball-maintained responding was stud- mg/kg) also produced cocaine-appropriate respond- ied for at least six months before these studies began. ing in monkeys trained to discriminate cocaine from sa- Monkeys received multiple vitamins, fresh fruit and line. Insofar as indatraline produced cocaine-like dis- vegetables and Lab Diet Jumbo Monkey Biscuits (PMI criminative stimulus effects, it may prove useful as a Feeds Inc., St. Louis, MO) to supplement a banana-fla- substitute agonist medication for cocaine abuse treat- vored pellet diet, fortified with vitamin C (P.J. Noyes ment (Negus et al. 1999; Rothman and Glowa 1995). Co., Lancaster, NH). Food supplements were given be- The long-acting mu opioid partial agonist buprenor- tween 5:00 and 5:30 p.m. Water was continuously avail- phine was selected for study because it has been shown able. A 12-hr light-dark cycle was in effect (lights on 7 to reduce heroin abuse in inpatient and outpatient clini- a.m.-7 p.m.), and the experimental chamber was dark cal studies (Johnson et al. 1992; Mello and Mendelson during food and drug self-administration sessions. 1980), and to reduce cocaine abuse by persons dually Animal maintenance and research were conducted dependent on cocaine and opioids (Gastfriend et al. in accordance with the guidelines provided by the Insti-

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tute of Laboratory Animal Resources (ILAR-NRC 1996). an FR4 (VR16:S) schedule resulted in presentation of a 1 The facility is licensed by the U.S. Department of Agri- g banana-flavored pellet (P.J. Noyes Co.). During drug culture, and protocols were approved by the Institu- self-administration sessions, the response key was illu- tional Animal Care and Use Committee. Monkeys were minated with a green light, and responding under an observed at least twice every day. Any changes in gen- FR4 (VR16:S) schedule resulted in delivery of 0.1 ml of eral activity were noted. The observer was not blind to saline or a drug solution over 1 sec through one lumen the treatment condition. In addition, the health of the of the double-lumen catheter. A 10-sec time-out fol- monkeys was periodically monitored by consultant vet- lowed delivery of each drug or saline injection or food erinarians trained in primate medicine. Operant food pellet. Schedules of reinforcement were implemented and drug acquisition procedures provided an opportu- using custom-designed software and IBM-compatible nity for enrichment and for monkeys to manipulate computers and interface systems (Med Associates, St. their environment (Line 1987). Monkeys had visual, au- Albans, VT). Additional details of this apparatus have ditory and olfactory contact with other monkeys been described previously (Mello et al. 1995). throughout the study. Four food sessions and four drug sessions were conducted during each experimental day. Food sessions began at 6 a.m., 11 a.m., 3 p.m., and 7 p.m., and drug ses- Surgical Procedures sions began at 7 a.m., 12 noon, 4 p.m,. and 8 p.m. At all Double lumen Silicone® rubber catheters (I.D. 0.028 in, other times, responding had no scheduled consequences. O.D. 0.088 in) (Saint Gobain Performance Plastics, Bea- The experimental room was dark during all food and verton, MI) were surgically implanted in the internal drug sessions. Each food and drug session lasted for one jugular or femoral vein and exited in the mid-scapular hour or until 25 food pellets or 20 injections had been de- region. All surgical procedures were performed under livered. Monkeys could earn a maximum of 100 food pel- aseptic conditions. Monkeys were initially sedated with lets per day and 80 injections per day. ketamine (5–10 mg/kg, i.m.), and anesthesia was induced with sodium thiopental (10 mg/kg, i.v.). Atro- Drug Self-Administration Procedures pine (0.05 mg/kg, s.c. or i.m.) was administered to reduce salivation. Following insertion of an endotracheal All monkeys were trained to self-administer cocaine tube, anesthesia was maintained with isofluorane (1– (0.032 mg/kg/inj, i.v.) and subsequently given access 2% mixed with oxygen). After surgery, monkeys were to speedball combinations of cocaine and heroin. Dur- given procaine penicillin G at 20,000 units/kg, i.m. ing speedball self-administration, cocaine and heroin twice daily for five days, or cephalexin 20 mg/kg, p.o. were prepared in a single solution and delivered twice daily for five days. An analgesic dose of bu- through one catheter lumen as in our previous studies prenorphine (0.032 mg/kg, i.m.) was administered (Mello and Negus 1998, 1999; Mello et al. 1995). Each twice daily for three days. cocaine or speedball injection was delivered in a vol- The intravenous catheter was protected by a tether ume of 0.10 ml over 1 sec. The simultaneous adminis- system consisting of a custom-fitted nylon vest con- tration of cocaine and heroin combinations was designed nected to a flexible stainless-steel cable and fluid swivel to simulate one type of speedball self-administration re- (Lomir Biomedical, Inc., Malone, NY). This flexible ported by humans (Schütz et al. 1994). tether system permits monkeys to move freely. Catheter patency was evaluated periodically by administration of Heroin and Cocaine (Speedball) Dose Combinations either a short-acting barbiturate, methohexital sodium (3 mg/kg), or ketamine (5 mg/kg) through the catheter The speedball combination selected for our initial stud- lumen. If muscle tone decreased within 10 sec after drug ies consisted of 0.01 mg/kg/inj cocaine in combination administration, the catheter was considered patent. with 0.0032 mg/kg/inj heroin. In our previous studies, these unit doses of cocaine alone and heroin alone each maintained high rates of drug self-administration at or Behavioral Procedures and Apparatus near the peak of the cocaine and heroin dose-effect Monkeys were housed individually in stainless steel curves (Mello and Negus 1998; Mello et al. 1995). Our chambers (64 ϫ 64 ϫ 79 cm) equipped with a custom- rationale for selecting a 3:1 ratio of cocaine to heroin designed operant response panel (28 ϫ 28 cm), a pellet was based on preliminary studies in which unit doses dispenser (Gerbrands Model G5210, Arlington, MA), of 0.01 mg/kg/inj cocaine and 0.0032 mg/kg/inj heroin and two syringe pumps (Model 981210, Harvard Appa- alone were the lowest doses that reliably maintained ratus, Inc., South Natick, MA), one for each lumen of drug self-administration in all monkeys under these ex- the double-lumen catheter. During food self-adminis- perimental conditions. Thus, cocaine was approxi- tration sessions, the response key on the operant panel mately 3-fold less potent than heroin as a reinforcer in was illuminated with a red light, and responding under rhesus monkeys.

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Indatraline, Buprenorphine, and Saline in rhesus monkeys (Mello and Negus 1998). The effects Administration Procedures of the highest doses of indatraline alone (0.32–0.56 mg/ kg/day) and buprenorphine alone (0.18 mg/kg/day) Saline, indatraline, and buprenorphine alone, and inda- on speedball self-administration were also examined. traline and buprenorphine in combination, were ad- In Experiment 2, a dose-effect curve for speedball self- ministered by slow infusion (0.10 ml/min) in a volume administration was determined. The speedball dose- of 5 ml through one lumen of the double lumen catheter effect curve consisted of the following cocaine and her- from 9:30 to 10:20 each morning. These procedures were oin combinations: 0.001 mg/kg/inj cocaine ϩ 0.00032 identical to those used in our previous studies of inda- mg/kg/inj heroin; 0.0032 mg/kg/inj cocaine ϩ 0.001 traline’s effects on cocaine self-administration (Negus mg/kg/inj heroin; 0.01 mg/kg/inj cocaine ϩ 0.0032 mg/ et al. 1999), buprenorphine’s effects on cocaine self- kg/inj heroin; 0.032 mg/kg/inj cocaine ϩ 0.01 mg/kg/ administration (Mello et al. 1989, 1990, 1992, 1993a,b), inj heroin. Each speedball dose combination was stud- and buprenorphine’s effects on heroin and speedball ied for 10 days during saline treatment. Then, the ef- self-administration (Mello and Negus 1998). For the re- fects of treatment with combinations of indatraline (0.56 maining 23 hr of each experimental day, 0.10 ml saline mg/kg/day) ϩ buprenorphine (0.18 mg/kg/day) on were delivered every 20 min to maintain catheter patency. the speedball dose-effect curve were evaluated in three monkeys in an own-control design. Each of three speedball dose combinations (0.001 mg/kg/inj cocaine ϩ 0.00032 Sequence of Indatraline ϩ Buprenorphine mg/kg/inj heroin; 0.0032 mg/kg/inj cocaine ϩ 0.001 mg/ Treatment Conditions kg/inj heroin; 0.01 mg/kg/inj cocaine ϩ 0.0032 mg/kg/inj The effects of daily treatment with saline or indatraline heroin) was available for 10 days during indatraline ϩ bu- and buprenorphine alone or in combination on speed- prenorphine treatment. ball- and food-maintained responding were studied. Each treatment condition was in effect for 10 days to evaluate the time course of any effects observed (see Drugs Mello and Negus 1996 for discussion). At the end of Cocaine HCl, heroin (3,6-diacetylmorphine HCl), and each treatment condition, monkeys were returned to sa- buprenorphine HCl were obtained in crystalline form line control treatment and the maintenance dose of co- from the National Institute on Drug Abuse, NIH. The caine for at least four days and until responding for co- purity of cocaine and heroin was certified by Research caine and food returned to baseline levels. This interval Triangle Institute, Research Triangle Park, NC, to be of saline treatment was designed to prevent any effects greater than 98%. Indatraline HCl (also known as Lu19- of one treatment condition from influencing the effects 005) was purchased from Research Biochemicals Inter- of a subsequent treatment condition. Cocaine (0.032 national (Natick, MA). All drugs were dissolved in ster- mg/kg/inj) was used as the maintenance drug to en- ile saline or sterile water, filter-sterilized using a 0.22 sure high baseline rates of drug-maintained responding micron Millipore filter, and stored in sterile, pyrogen- before each treatment condition began. The same proce- free vials. All doses are expressed for the salt forms of dures were used in our previous reports of treatment the drugs described above. medication effects on speedball self-administration (Mello and Negus 1998, 1999). Speedball combinations were substituted for the maintenance dose of cocaine in Data Analysis an irregular order. In Experiment 1, the effects of indatraline alone, bu- The dependent variables were the number of saline or prenorphine alone, and indatraline ϩ buprenorphine speedball injections per day and the number of food combinations on responding maintained by food and a pellets per day. Statistical analyses were based on the single dose of speedball (0.01 mg/kg/inj cocaine ϩ mean (Ϯ S.E.M.) number of injections and food pellets 0.0032 mg/kg/inj heroin) were examined in five mon- per day delivered over the entire 10 days of each treat- keys. Indatraline ϩ buprenorphine were administered ment condition. Changes in drug- and food-maintained in combinations consisting of a 3:1 ratio of indatraline responding during treatment with indatraline and bu- to buprenorphine (0.10 mg/kg/day indatraline ϩ 0.032 prenorphine administered alone or in combination mg/kg/day buprenorphine to 0.56 mg/kg/day inda- were statistically compared with the saline treatment traline ϩ 0.18 mg/kg/day buprenorphine). These rela- baseline with an ANOVA for repeated measures and tive and absolute doses of indatraline ϩ buprenorphine Contrast tests or Fishers post-hoc tests. Huynh-Feldt were based on our previous studies that examined Epsilon factors were used to adjust for degrees of free- the potency of indatraline in decreasing cocaine self- dom of within-group means (Super ANOVA Software administration (Negus et al. 1999) and the potency of Manual, Abacus Concepts, Inc., Berkeley, CA; 1989). In buprenorphine in decreasing heroin self-administration addition, the mean numbers of injections and food pel-

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Figure 1. Effects of 10 days of treatment with saline, ascending doses of indatraline ϩ buprenorphine combinations, and indatraline or buprenorphine alone on speedball- and food-maintained responding. Speedball- and food-maintained responding are shown as open rectangles during saline treatment, as closed rectangles during treatment with indatraline ϩ buprenorphine combinations, as grey rectangles during treatment with indatraline alone and as a striped rectangle during treatment with buprenorphine alone. Saline and doses of indatraline and buprenorphine (mg/ kg/day) are shown on the abscissae. The average number of speedball injections per day (row 1) or food pellets per day (row 2) are shown on the left ordinates. Speedballs consisted of a unit dose of cocaine (0.01 mg/kg/inj) and heroin (0.0032 mg/kg/inj) in combination. Each data point represents the average number of injections or food pellets (Ϯ S.E.M.) during 10 consecutive days of saline or drug treatment in a group of four or five monkeys (left panel), or three monkeys (right panel). The asterisks indicate a significant change from the saline treatment baseline (* ϭ p Ͻ .05; ** ϭ p Ͻ .01; *** ϭ p Ͻ .001).

lets delivered each day during a 10-day medication or day buprenorphine produced no change in speedball- saline treatment condition are shown graphically for maintained responding and an increase in food-main- each speedball combination. Daily patterns of speed- tained responding. When 0.32 mg/kg/day indatraline ball- and food-maintained responding were compared was administered in combination with 0.10 mg/kg/ with ANOVA for repeated measures on corresponding day buprenorphine, speedball injections decreased sig- days during saline treatment and indatraline ϩ bu- nificantly in comparison to saline treatment baseline prenorphine treatment. levels (p Ͻ .01). Food-maintained responding also decreased, but this change was not significantly different from saline RESULTS treatment baseline levels. When 0.056 mg/kg/day indatraline was given in combination with 0.18 mg/kg/ Experiment 1: Effects of 10 Days Indatraline ϩ day buprenorphine, speedball and food self-adminis- Buprenorphine Treatment on Speedball- and tration both decreased significantly in comparison to Food-Maintained Responding the saline treatment baseline (p Ͻ .05–.001). In contrast, Figure 1 shows the effects of 10 consecutive days of when the same doses of indatraline alone (0.32 or 0.056 treatment with saline, combinations of indatraline ϩ bu- mg/kg/day) or buprenorphine alone (0.18 mg/kg/day) prenorphine, and indatraline and buprenorphine alone were administered, speedball and food self-administra- on speedball- (row 1) and food-maintained responding tion did not decrease significantly relative to saline treat- (row 2). During the saline baseline treatment, monkeys ment baseline levels. Although speedball-maintained re- self-administered an average of 71 (Ϯ4) (mean Ϯ sponding was higher during treatment with 0.32 mg/ S.E.M.) speedball injections per day and 61 (Ϯ7) (mean kg/day indatraline alone and 0.18 mg/kg/day bu- Ϯ S.E.M.) food pellets per day. Treatment with a combi- prenorphine alone than during combined indatraline nation of 0.10 mg/kg/day indatraline ϩ 0.032 mg/kg/ and buprenorphine treatment, these differences were not

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statistically significant. Food-maintained responding did decreases in speedball-maintained responding were not differ significantly from the saline treatment baseline sustained throughout the 10-day treatment period, but during treatment with indatraline alone and tended to food-maintained responding returned to baseline levels increase during treatment with buprenorphine alone. after two days. At the highest dose studied (0.56 mg/ Figure 2 shows the average number of speedball in- kg/day indatraline ϩ 0.18 mg/kg/day buprenorphine), jections and food pellets delivered each day during the speedball- and food-maintained responding decreased 10 days of treatment with saline, or combinations of in- significantly below baseline throughout the 10-day treat- datraline (0.10, 0.32, 0.56 mg/kg/day) ϩ buprenorphine ment period (p Ͻ.05–.001). After two days of indatraline ϩ (0.032, 0.10, 0.18 mg/kg/day). During saline treatment, buprenorphine treatment, speedball self-administration speedball-maintained responding averaged between 66 Ϯ decreased to 0 injections per day in two monkeys. After 5 and 78 Ϯ 2 injections per day and food-maintained re- five days of indatraline ϩ buprenorphine treatment, sponding averaged between 53 Ϯ 7 and 68 Ϯ 13 pellets per speedball self-administration decreased to between 0 and day. Patterns of both speedball- and food-maintained re- 5 injections per day in four of the five monkeys studied. sponding were relatively stable across the 10 days of saline treatment. Speedball- and food-maintained responding Experiment 2: Effects of 10 Days of Treatment with during saline treatment were compared with correspond- Indatraline ϩ Buprenorphine Combinations on the ing days during treatment with indatraline ϩ buprenor- Speedball Dose-Effect Curve phine. When 0.10 mg/kg/day indatraline ϩ 0.032 mg/kg/ day buprenorphine were administered in combination, Saline Treatment. Figure 3 shows the effects of treat- there was an initial decrease in both speedball- and food- ment with saline or with a combination of indatraline maintained responding that was not sustained. (0.56 mg/kg/day) and buprenorphine (0.18 mg/kg/ Food-maintained responding gradually increased day) on the speedball dose-effect curve [left panel] and and was significantly higher on days 4-10 than on cor- concurrent food-maintained responding [right panel]. responding days during the saline treatment baseline During saline treatment, when saline was available for (p Ͻ .05–.001). A higher dose of 0.32 mg/kg/day inda- self-administration, monkeys took an average of 20 Ϯ 4 traline ϩ 0.18 mg/kg/day buprenorphine reduced both (mean Ϯ S.E.M.) injections per day and 87 Ϯ 7 (mean Ϯ speedball- and food-maintained responding signifi- S.E.M.) food pellets per day. When a 3:1 cocaine/heroin cantly below saline treatment levels (p Ͻ .05–.001). The speedball combination was available during saline con-

Figure 2. Effects of chronic treatment with saline or indatraline ϩ buprenorphine combinations on daily speedball- and food-maintained responding. Consecutive days of treatment are shown on the abscissae. Speedball injections per day are shown on the left ordinate and food pellets per day are shown on the right ordinate. Speedballs consisted of a unit dose of cocaine (0.01 mg/kg/inj) and heroin (0.0032 mg/kg/inj) in combination. Average speedball and food self-administration per day (Ϯ S.E.M.) during 10 days of saline treatment are shown as open circles and during combined indatraline ϩ buprenorphine treatment are shown as closed symbols. Indatraline ϩ buprenorphine doses are shown as follows: closed tri- angles, 0.10 ϩ 0.032 mg/kg/day; closed squares, 0.32 ϩ 0.10 mg/kg/day; closed circles, 0.56 ϩ 0.18 mg/kg/day. Each data point is based on four or five monkeys. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Speedball and Indatralime/Burprenorphine 111

trol treatment, the speedball dose-effect curve had an for these two speedball doses during indatraline ϩ bu- inverted-U shape. Speedball doses of 0.0032 mg/kg/inj prenorphine treatment was equivalent to or lower than cocaine ϩ 0.001 mg/kg/inj heroin to 0.01 mg/kg/inj saline-maintained responding during saline treatment. cocaine ϩ 0.0032 mg/kg/inj heroin each maintained sig- Food-maintained responding during treatment with in- nificantly more responding than saline (p Ͻ .05–.001). A datraline ϩ buprenorphine did not differ significantly unit dose of 0.0032 mg/kg/inj cocaine ϩ 0.001 mg/kg/ from levels of food-maintained responding during saline inj heroin was at the peak of the speedball dose-effect treatment. There was a similar speedball dose-dependent curve and maintained 74 Ϯ 4 (mean Ϯ S.E.M.) speed- decrease in the average number of food pellets per day ball injections per day. During saline treatment, there during indatraline ϩ buprenorphine and saline treatment. was a speedball dose-dependent decrease in food- Figure 4 shows daily patterns of speedball- and maintained responding. At the highest speedball doses food-maintained responding during 10 days of treat- (0.32 mg/kg/inj cocaine ϩ 0.01 mg/kg/inj heroin), ment with saline or a combination of 0.56 mg/kg/day food-maintained responding was significantly below indatraline ϩ 0.18 mg/kg/day buprenorphine. The two levels during saline self-administration (p Ͻ .05). speedball doses are from the ascending limb of the speedball dose-effect curve shown in Figure 3. During Indatraline ϩ Buprenorphine Treatment. Treatment saline treatment, the lowest speedball dose studied with the 0.56 mg/kg/day indatraline ϩ 0.18 mg/kg/ (0.001 mg/kg/inj cocaine ϩ 0.00032 mg/kg/inj) did not day buprenorphine combination produced a down- maintain responding significantly above saline levels. ward shift in the peak of the speedball self-administra- Figure 4 shows that speedball-maintained responding tion dose-effect curve. The two speedball unit doses decreased from 69 Ϯ 7 injections on day 1 to 26 Ϯ 7 in- that were at the peak of the dose-effect curve during sa- jections on day 10 (row 1, left panel). During treatment line treatment maintained significantly lower levels of with indatraline ϩ buprenorphine, speedball injections speedball self-administration during indatraline ϩ bu- were significantly lower than during saline treatment prenorphine treatment (p Ͻ .02). Moreover, responding on days 1, 3, 4, and 6 (p Ͻ .05). Speedball self-adminis-

Figure 3. Effects of 10 days of treatment with saline or an indatraline ϩ buprenorphine combination on speedball dose- effect curves. Dose-effect curves for speedball combinations of cocaine (0.001–0.10 mg/kg/inj) and heroin (0.00032–0.032 mg/kg/inj) are shown for a group of three monkeys (left panel). The unit doses of each cocaine and heroin combination are shown on the abscissa. Injections per day are shown on the left ordinate. Points above “Saline” show data from saline treatment sessions when saline was the solution available for self-administration. Self-administration of each cocaine-heroin combination during saline treatment (open circles) is shown at the left. Speedball self-administration during treatment with an indatraline (0.56 mg/kg/day) ϩ buprenorphine (0.18 mg/kg/day) combination is shown as black circles. Each data point is the average of 10 days of speedball or food self-administration (Ϯ S.E.M.). Food-maintained responding during saline self- administration and self-administration of speedball cocaine and heroin combinations during saline treatment (open circles) is shown in the right panel. The number of food pellets self-administered per day is shown on the right ordinate. Food-maintained responding during treatment with indatraline (0.56 mg/kg/day) ϩ buprenorphine (0.18 mg/kg/day) is shown as black circles. The daggers indicate a significant difference from saline self-administration during saline treatment († ϭ p Ͻ.05; †† ϭ p Ͻ .01). The asterisks indicate that the number of speedball injections self-administered at the same speedball dose combinations were significantly different during saline treatment and indatraline ϩ buprenorphine treatment (** ϭ p Ͻ .01). 112 N.K. Mello and S.S. Negus NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1

tration decreased to 1 injection per day by the third day responding decreased significantly below saline treat- of treatment and remained low throughout the remain- ment levels on the first day of indatraline ϩ buprenor- der of the treatment period (Figure 4, row 1, left panel). phine treatment (p Ͻ .001) and remained significantly During saline treatment, food-maintained responding av- below saline treatment levels for 10 days (p Ͻ .001) (Fig- eraged between 85 and 93 pellets per day (Figure 4, row 1, ure 4, row 2, left). Food-maintained responding was right panel). On the first day of indatraline ϩ buprenor- also significantly below saline treatment baseline levels phine treatment, food-maintained responding was signifi- for the first three days of indatraline ϩ buprenorphine cantly below saline treatment levels (p Ͻ .05). After five treatment (p Ͻ .01–.001), then gradually returned to- days of treatment, food-maintained responding gradually wards baseline levels (Figure 4, row 2, right panel). returned to baseline levels (Figure 4, row 1, right panel). Responding maintained by 0.0032 mg/kg/inj co- Other Effects of Chronic Indatraline and Buprenor- caine ϩ 0.001 mg/kg/inj heroin, the speedball dose phine Treatment. Chronic administration of indatra- that was at the peak of the dose-effect curve, varied be- line alone and the highest doses of indatraline ϩ bu- tween 80 and 62 injections per day during saline treat- prenorphine was associated with some hyperactivity ment (Figure 4, row 2, left panel). Speedball-maintained (stereotypic grooming, scratching, visual checking) in

Figure 4. Effects of chronic treatment with saline and an indatraline ϩ buprenorphine combination on daily speedball- and food- maintained responding. The unit doses of each cocaine and heroin speedball combination are shown in the grey boxes in the center of each row. Speedball injections per day are shown on the left ordinate and food pellets per day are shown on the right ordinate. Speedball-maintained responding during 10 days of saline treatment is shown as open circles. Speedball-maintained responding during 10 days of indatraline (0.56 mg/kg/day) ϩ buprenorphine (0.18 mg/kg/day) treatment is shown as closed circles (left panel). Food-maintained responding during 10 days of saline treatment is shown as open squares. Food-maintained responding during 10 days of indatraline (0.56 mg/kg/day) ϩ buprenorphine (0.18 mg/kg/day) treatment is shown as closed squares (right panel). Con- secutive days of treatment are shown on the abscissae. Each data point is based on the same three monkeys studied as their own control across treatment conditions. Asterisks indicate statistically significant differences in speedball- or food-maintained responding on corresponding days during saline treatment and indatraline ϩ buprenorphine treatment (* ϭ p Ͻ .05; ** ϭ p Ͻ .01; *** ϭ p Ͻ .001). NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Speedball and Indatralime/Burprenorphine 113

all five monkeys. No sedation or hyperactivity was ob- speedball self-administration in the present study dif- served during treatment with buprenorphine alone or fered from those of flupenthixol ϩ quadazocine in our lower doses of indatraline ϩ buprenorphine combina- previous study in several respects (Mello and Negus tions (0.10 mg/kg/day indatraline ϩ 0.032 mg/kg/day 1999). First, the effects of indatraline ϩ buprenorphine buprenorphine to 0.32 mg/kg/day indatraline ϩ 0.10 on speedball-maintained responding were usually sus- mg/kg/day buprenorphine). tained across 10 days of treatment, whereas the effects of flupenthixol ϩ quadazocine were usually transient (Mello and Negus 1999). Sustained reductions in the DISCUSSION self-administration of cocaine alone have been observed for periods up to four months during buprenor- Effects of Indatraline ϩ Buprenorphine phine treatment (Mello et al. 1992) and for up to seven Combinations on Speedball Self-Administration days (the longest period evaluated) during treatment Although cocaine and opioids produce some interact- with indatraline alone (Negus et al. 1999). The transient ing effects, the abuse-related effects of cocaine and opi- effects of the flupenthixol ϩ quadazocine combination oids appear to remain functionally independent of each probably reflect the fact that dopamine antagonists of- other when combined in a speedball (Hemby et al. 1996, ten have transient effects on cocaine self-administration 1999; Mello and Negus 1999; Negus et al. 1998a). Ac- alone (Kleven and Woolverton 1990; Negus et al. 1996; cordingly, we hypothesized that a combination of med- Richardson et al. 1994). ications targeted at both the stimulant and opioid com- A second major difference between the effects of ponents of the speedball might be effective in treatment with indatraline ϩ buprenorphine combina- attenuating the reinforcing effects of this type of multi- tions and flupenthixol ϩ quadazocine combinations on ple drug self-administration (Mello and Negus 1999). speedball-maintained responding was in the direction This is the first evaluation of the combined effects of of changes in the speedball dose-effect curve. Flu- two potential agonist substitution medications, the do- penthixol ϩ quadazocine treatment produced a 3-fold pamine reuptake inhibitor indatraline and the mu opi- rightward shift in the speedball dose-effect curve and oid partial agonist buprenorphine, on speedball (co- slightly increased self-administration of high speedball caine ϩ heroin) self-administration by rhesus monkeys. doses (Mello and Negus 1999). In contrast, indatraline ϩ Our major finding was that chronic administration of buprenorphine decreased speedball self-administra- an indatraline ϩ buprenorphine combination produced tion across the range of speedball doses examined. We significant and sustained decreases in self-administra- have suggested elsewhere that a downward shift in a tion of speedballs at the peak of the dose-effect curve. drug self-administration dose-effect curve may have Moreover, an indatraline ϩ buprenorphine combina- the greatest therapeutic utility, because there is a de- tion produced a significant downward shift in the speed- crease in drug-taking behavior across a broad range of ball self-administration dose-effect curve. In contrast, 10 unit doses (Mello and Negus 1996). In contrast, medica- days of treatment with the same doses of indatraline tions that produce a rightward shift in the drug dose- alone and buprenorphine alone did not reduce speedball effect curve simply alter the potency of the abused drug. self-administration significantly. Indatraline ϩ buprenor- Thus, increases in the unit dose of the abused drug, or phine combinations also did not increase self-adminis- increases in the rate of drug self-administration, could tration of speedballs that maintained low rates of re- negate the effect of the medication on drug-maintained sponding during saline control treatment. These data responding (Mello and Negus 1996). The effects of inda- suggest that indatraline ϩ buprenorphine combinations traline ϩ buprenorphine on self-administration of high did not enhance the reinforcing efficacy of low doses of speedball doses on the descending limb of the speedball speedballs, but rather reduced the reinforcing effects of dose-effect curve were not examined in the present speedballs across a broad dose range. study. However, it is likely that indatraline ϩ buprenor- These findings are consistent with our earlier reports phine would also have decreased high dose speedball that pretreatment with combinations of a non-selective self-administration because indatraline decreases high dopamine antagonist flupenthixol and an opioid antag- dose cocaine self-administration and buprenorphine de- onist quadazocine dose-dependently antagonized both creases high dose heroin self-administration (Mello and the reinforcing and discriminative stimulus effects of Negus 1998; Negus et al. 1999). speedballs, whereas administration of the same doses A third difference between the behavioral effects of of flupenthixol alone or quadazocine alone was less ef- indatraline ϩ buprenorphine combinations and the flu- fective (Mello and Negus 1999; Negus et al. 1998a). penthixol ϩ quadazocine combinations was in the type Speedball self-administration was maintained by a 3:1 and severity of adverse side effects produced during cocaine-heroin combination in that study (Mello and chronic treatment. Indatraline ϩ buprenorphine pro- Negus 1999) and in the present study. However, the ef- duced hyperactivity reflected in stereotypic grooming, fects of indatraline ϩ buprenorphine combinations on scratching and visual checking; behaviors similar to 114 N.K. Mello and S.S. Negus NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1

those previously observed during chronic treatment buprenorphine alone often attenuated the rate-decreas- with indatraline alone (0.32–1.0 mg/kg/day) (Negus et ing effects of heroin and speedball self-administration al. 1999). In contrast, flupenthixol ϩ quadazocine pro- on food-maintained responding (Mello and Negus duced transient mild sedation reflected in decreased lo- 1998). Taken together, these findings suggest that opi- comotor activity and unresponsiveness to preferred oid partial agonists and antagonists readily antagonize foods (Mello and Negus 1999). Sedation usually accom- the rate-decreasing effects of opioid agonists, whereas panies administration of dopamine antagonists to dopamine reuptake inhibitors and dopamine antago- rhesus monkeys (Negus et al. 1996; Winger 1994; see nists are less effective in blocking the rate-decreasing Mello and Negus 1996 for review). The implications of effects of cocaine and may also produce rate-decreasing these adverse side effects for the clinical treatment of effects of their own (Mello and Negus 1998, 1999; Ne- polydrug abuse remain to be determined. gus et al. 1999; see Mello and Negus 1996 for review).

Effects of Indatraline and Buprenorphine on Food- Maintained Responding Effects of Indatraline and Buprenorphine Alone on Speedball Self-Administration Treatment with 0.32 mg/kg/day indatraline ϩ 0.10 mg/kg/day buprenorphine selectively decreased Indatraline alone did not significantly reduce speed- speedball self-administration with no significant de- ball-maintained responding, whereas in our previous crease in food-maintained responding, whereas a study, indatraline produced dose-dependent and sus- higher dose of indatraline ϩ buprenorphine decreased tained decreases in cocaine self-administration across a both speedball- and food-maintained responding. broad range of cocaine doses (Negus et al. 1999). More- However, decreases in food-maintained responding over, indatraline produced downward shifts in cocaine were usually transient and began to return toward self-administration dose-effect curves (Negus et al. baseline levels after five days of treatment whereas de- 1999). Indatraline is a relatively non-selective mono- creases in speedball-maintained responding were sus- amine reuptake inhibitor (Bogeso et al. 1985; Hyttel and tained. These findings suggest that indatraline ϩ bu- Larsen 1985), and it is possible that more selective do- prenorphine combinations selectively decreased pamine reuptake inhibitors in combination with bu- speedball self-administration. However, interpretation prenorphine might be even more effective in reducing of the relative selectivity of indatraline ϩ buprenor- speedball self-administration. For example, it has been phine effects on speedballs and food is complicated by reported that more selective dopamine reuptake inhibi- the fact that there was also a speedball dose-dependent tors produce downward shifts in the cocaine self-ad- decrease in food-maintained responding during saline ministration dose-effect curve with minimal effects on treatment. These results are consistent with our previ- food-maintained responding (Dworkin et al. 1998; ous reports that self-administration of various speed- Glowa et al. 1995a,b, 1996). However, dopamine re- ball combinations, as well as cocaine alone and heroin uptake inhibitors also produce non-selective behavioral alone, produced dose-dependent decreases in food- effects such as hyperactivity and stereotypies, which maintained responding under experimental conditions may decrease operant responding maintained by both identical to those reported here (Mello and Negus 1998; drug and non-drug reinforcers (Negus et al. 1999). Mello et al. 1995; Negus et al. 1995). Although indatra- These non-selective behavioral effects may have con- line ϩ buprenorphine treatment appeared to reduce the tributed to the reductions in speedball self-administra- reinforcing effects of speedballs, it did not significantly tion observed at the beginning of indatraline treatment. alter the direct rate-decreasing effects of speedballs on We are unaware of any studies of the effects of dopa- food-maintained responding. mine reuptake inhibitors on opioid self-administration. We previously reported that treatment with a flu- In our previous studies, buprenorphine alone re- penthixol ϩ quadazocine combination also did not at- duced cocaine self-administration (Mello et al. 1989, tenuate speedball-induced decreases in food-main- 1990, 1992, 1993a,b) as well as opioid self-administra- tained responding (Mello and Negus 1999). However, tion (Mello et al. 1983; Mello and Negus 1998) under the quadazocine appeared to antagonize the rate-decreas- same schedule of reinforcement and sequence of daily ing effects of the heroin component of the speedball, be- drug and food sessions as in the present study. How- cause the highest rates of food-maintained responding ever, buprenorphine alone (0.18 mg/kg/day) did not were observed during treatment with quadazocine reduce responding maintained by a speedball combina- alone (Mello and Negus 1999). In the present study, bu- tion of 0.01 mg/kg/inj cocaine and 0.0032 mg/kg/inj prenorphine also appeared to antagonize the rate- heroin in the present study. These data are consistent decreasing effects of heroin because food-maintained with our previous report that buprenorphine (0.075 or responding was highest during treatment with bu- 0.75 mg/kg/day) also did not decrease self-administra- prenorphine alone. Similarly, chronic treatment with tion of the same speedball cocaine ϩ heroin dose com- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Speedball and Indatralime/Burprenorphine 115

bination (Mello and Negus 1998). As noted earlier, chronic data were reported at the 1999 annual meeting of the College treatment with buprenorphine alone (0.237 mg/kg/day) on Problems of Drug Dependence. This research was sup- shifted dose-effect curves for speedball combinations of ported in part by KO5 DA-00101, P50 DA-04059, and RO1 DA-02519 from the National Institute on Drug Abuse, NIH. cocaine (0.001 mg/kg/inj) and heroin (0.0001–0.032 mg/ kg/inj) downwards and approximately 1 log unit to the right (Mello and Negus 1998). However, the same dose of REFERENCES buprenorphine was less effective in decreasing responding maintained by speedball combinations of heroin Bogeso KP, Christensen AV, Hyttel J, Liljefors T (1985): 3 (0.0001–0.10 mg/kg/inj) and higher doses of cocaine (0.01 Phenyl-1-indanamines: Potential antidepressant activity and 0.1 mg/kg/inj) (Mello and Negus 1998). and potent inhibition of dopamine, norepinephrine and serotonin uptake. J Med Chem 28:1817–1828 Condelli WS, Fairbank JA, Dennis ML, Rachal JV (1991): Implications for Polydrug Abuse Treatment Cocaine use by clients in methadone programs: Signifi- The reinforcing and the discriminative stimulus effects cance, scope, and behavioral interventions. J Subst Abuse Treat 8:203–212 of speedballs appear to reflect some aspects of both the opioid and stimulant component drugs. Our finding Corrigall WA, Coen KM (1991): Cocaine self-administration is increased by both D1 and D2 dopamine antagonists. that speedball self-administration was reduced more ef- Pharmacol Biochem Behav 39:799–802 fectively by a combination of indatraline and buprenor- Dworkin SI, Lambert P, Sizemore GM, Carroll FI, Kuhar MJ phine doses than by either drug dose alone confirms (1998): RTI-113 administration reduces cocaine self- and extends our previous finding with flupenthixol and administration at high occupancy of dopamine trans- quadazocine (Mello and Negus 1999). Taken together, porter. Synapse 30:49–55 these data suggest that medications targeted at the co- Foltin RW, Christiansen I, Levin FR, Fischman MW (1995): caine and heroin components of the speedball may re- Effects of single and multiple intravenous cocaine injec- duce speedball self-administration with higher potency tions in humans maintained on methadone. J Pharma- or greater efficacy when they are administered in com- col Exp Ther 275:38–47 bination than when they are administered alone. This Foltin RW, Fischman MW (1992): The cardiovascular and sub- approach is consistent with the fact that cocaine and opioid jective effects of intravenous cocaine and morphine combinations in humans. J Pharmacol Exp Ther 261:623–632 components are primarily mediated by different receptor mechanisms. The contribution of dopaminergic activity to Gastfriend DR, Mendelson JH, Mello NK, Teoh SK, Reif S the abuse-related effects of cocaine is well documented (1993): Buprenorphine pharmacotherapy for concurrent heroin and cocaine dependence. Am J Addict 2:269–278 (Koob and Bloom 1988; Kuhar et al. 1991; Ritz et al. 1987; Woolverton and Johnson 1992) but dopamine’s role in the Glowa JR, Wojinicki FHE, Matecka D, Rice KC, Rothman RB (1996): Sustained decrease in cocaine-maintained reinforcing effects of opioids has not been clearly estab- responding in rhesus monkeys with 1-[2-[bis (4-fluo- lished (Hemby et al. 1995, 1999). Similarly, mu opioid re- rophenyl)methoxy]ethyl]-4-(3-hydroxy-3-hydroxy-3-phe- ceptor activity is important for the reinforcing effects of nylpropyl) piperaxinyl decanoate, a long-acting ester opioids, but not of cocaine (Negus and Dykstra 1989). derivative of GBR 12909. J Med Chem 39:4628–4691 Studies with receptor-selective antagonists indicate Glowa JR, Wojnicki FHE, Matecka D, Bacher JD, Mansbach that dopamine antagonists usually alter the reinforcing RS, Balster RL, Rice KC (1995a): Effects of dopamine and discriminative stimulus effects of cocaine but not of reuptake inhibitors on food- and cocaine-maintained responding. I. Dependence on unit dose of cocaine. Exp opioids, whereas mu opioid antagonists alter the reinforc- Clin Psychopharmacol 3:219–231 ing and discriminative stimulus effects of opioids but not Glowa JR, Wojnicki FHE, Matecka D, Rice KC, Rothman RB of cocaine (Mello et al. 1995; Negus et al. 1996; Platt et al. (1995b): Effects of dopamine reuptake inhibitors on 1999; see Mello and Negus 1996 for review). The present food- and cocaine-maintained responding. II. 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